The major focus of the laboratory is on drug resistance, seeking basic science approaches to reversal or prevention of resistance which will lead to improved antineoplastic therapy in the clinic. We have studied P- glycoprotein (Pgp) most extensively, characterizing regulation of expression and function. The role of different protein kinases in phosphorylating Pgp has been examined, and the effect of inhibitors on function. We have examined expression of Pgp in human tumor samples, seeking correlations between expression and Pgp function; and between expression and response to antagonist therapy in the clinic. Over 40 patients have been enrolled in a Phase I trial of the Pgp antagonist, PSC 833, plus vinblastine. This study has defined the maximum tolerated dose of PSC 833. Other laboratory studies have focused upon exploring non-Pgp mediated mechanisms of drug resistance. Alterations in growth factor pathways are common in drug resistant human breast cancer cells; studies are in progress to learn how these changes could influence drug resistance. The enhanced signal transduction does not appear to enhance growth rate, but instead could effect resistance through cell cycle or apoptosis pathways. Finally, we are attempting to identify a novel drug transporter in human breast cancer cells. The subline under study does not overexpress MRP or P-glycoprotein; it exhibits rhodamine and daunomycin efflux and cross-resistance to multiple anthracyclines. We are currently pursuing molecular and biochemical strategies for identifying this protein. This offers the hope of identifying in breast cancer a transport protein with anthracycline specificity, which is able to reduce the intracellular accumulation of anthracyclines and promote resistance.